Malignant primary brain tumors represent the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Glioblastoma (GBM) is uniformly lethal, and current therapy is non-specific and produces a median overall survival of <15 months. In contrast, immunotherapeutic approaches are exquisitely precise and can eradicate large, well-established tumors in mice and humans even when tumors reside within the immunologically privileged brain. However, immunotherapy is limited by the lack of frequent and homogeneously-expressed tumor-specific antigens. We have previously demonstrated that a peptide vaccine targeting the tumor-specific EGFRvIII mutation (PEPvIII) induces immune responses sufficient to eliminate all EGFRvIII-expressing tumor cells in mice and humans without toxicity. Unfortunately, EGFRvIII is heterogeneously expressed and tumors recur as a result of outgrowth of the EGFRvIII negative tumor cells. However, the nearly universal presence and homogeneous expression of cytomegalovirus (CMV) antigens in GBM, but not normal brain, has now been well-established and provides an unparalleled opportunity to subvert these immunogenic viral proteins as tumor-specific targets. In two consecutive clinical trials from our laboratory using dendritic cells (DCs) targeting CMV pp65 in patients with GBM, specific immunologic responses were induced along with remarkably enhanced progression free survival and overall survival. However, DC vaccination is expensive, time-consuming, and commercialization is challenging. In contrast, peptide vaccines are cost-effective, easier to produce, and easier to commercialize. Leveraging our experience with PEPvIII, we have developed a CMV-specific multi-epitope peptide cocktail (PEP-CMV). PEP-CMV vaccination is immunogenic in HLA-A2 transgenic mice and peripheral blood mononuclear cells from CMV seropositive patients with GBM respond to stimulation with PEP-CMV, indicating PEP-CMV is broadly immunogenic in our patient population. We have already shown with PEPvIII that lymphopenia induced by both standard of care temozolomide (TMZ) and dose intensified TMZ can be leveraged to augment immunogenicity and the impact these regimens have on PEP-CMV immunogenicity will be compared in our proposed trial. Additionally, we will examine a novel immunostimulant, tetanus (Td), as an adjuvant to PEP-CMV. In a recent pilot trial from our laboratory, patients randomized to receive Td as vaccine- site pre-conditioning prior to CMV pp65-loaded DC immunization, experienced significantly enhanced PFS and OS in comparison to the control arm. A Td booster was included for site pre-conditioning during PEP-CMV immunogenicity analysis and was demonstrated to significantly enhance IFN secretion of CMV targeted T cells in HLA-A2 transgenics. Therefore, in this proposal, we will test the HYPOTHESIS that vaccination with PEP-CMV after Td skin conditioning will be a feasible, safe, and immunogenic tumor-specific therapy in patients with newly-diagnosed GBM during TMZ chemotherapy, without antigen escape or toxicity.